Copolymer compositions adapted for use in controlled release delivery systems such as biodegradable and bioerodible implants are known. See, for example, U.S. Pat. Nos. 7,019,106; 6,565,874; 6,528,080; RE37,950; 6,461,631; 6,395,293; 6,355,657; 6,261,583; 6,143,314; 5,990,194; 5,945,115; 5,792,469; 5,780,044; 5,759,563; 5,744,153; 5,739,176; 5,736,152; 5,733,950; 5,702,716; 5,681,873; 5,599,552; 5,487,897; 5,340,849; 5,324,519; 5,278,202; and 5,278,201. Such controlled release systems are in general advantageous because they provide for the controlled and sustained release of medications, often directly at or near the desired site of action, over the period of days, weeks or even months. Controlled release systems can include polymer matrices that are known to be broken down in the body by various endogenous substances such as enzymes and body fluids, such as polyesters including poly-lactide, poly-glycolide, and copolymers thereof (“PLG copolymers”) prepared from glycolide (1,4-dioxan-2,5-dione, glycolic acid cyclic dimer lactone) and lactide (3,6-dimethyl-1,4-dioxan-2,5-dione, lactic acid cyclic dimer lactone), or from glycolate (2-hydroxyacetate) and lactate (2-hydroxypropionate). These copolymer materials are particularly favored for this application due to their facile breakdown in vivo by body fluids or enzymes in the body to non-toxic materials, and their favorable properties in temporally controlling the release of medicaments and biologically active agents (“bioactive agents”) that may be contained within a mass of the controlled release formulation incorporating the polymer that has been implanted within a patient's body tissues. Typically, controlled release systems are adapted to provide for as constant a rate of release as possible of the bioactive agent over the time period that the implant persists within the body.
Flowable delivery systems, such as the Atrigel® system, are disclosed in U.S. Pat. Nos. 6,565,874, 6,528,080, 6,461,631, 6,395,293, and references found therein. Flowable delivery systems like the Atrigel® system include a biodegradable polymer, a bioactive agent, and an organic solvent that has at least a very slight solubility in body fluids. When the substantially liquid (“flowable”) solution of the delivery system is injected into a patient's tissues, typically as a single bolus, the organic solvent diffuses into surrounding body fluids, causing precipitation or gelation of the water-insoluble polymer containing the bioactive agent. It is believed that initially a “skin” forms on the deposited liquid mass, bringing about formation of the semi-solid deposit known as a depot that contains the remaining solution of the polymer and the bioactive agent in the solvent. As the depot resides in the tissues, the solvent continues to diffuse out and body fluids continue to diffuse in, bringing about ongoing precipitation of the polymer with the bioactive agent, until a gelled or solid mass remains. Channels or pores may form in the depot as part of this process. Due to the biodegradable nature of the polymer in the presence of body fluids and of enzymes within the body, the polymer slowly degrades into soluble non-toxic hydrolysis products, releasing the contained bioactive agent over a period of time. This process continues until the depot is substantially completely dissolved and all the bioactive agent is released. It is understood that such depots can be adapted to persist for various lengths of time within the body, such as about 30 days, about 60 days, or about 3 months, 4 months, or 6 months.
Polyalkyleneglycols, such as polyethyleneglycol, are well known substances formed by the polymerization of alkylene oxides, such as ethylene oxide. Despite their often high molecular weights, ranging up into the hundreds of thousands, and their non-ionic nature, they tend to have a high degree of solubility in water due to the abundance of oxygen atoms in their structures, which are available to enter into hydrogen bonding interactions with water molecules. Polyethyleneglycol groups are known to interact with proteins with minimal irreversible absorption of the protein by the polyethyleneglycol (J H Lee, J Kopecek, J D Andrade (1989), J. Biomed. Mater. Res., 23, 351-368). Thus, polyethyleneglycols are also known to interact with proteins in beneficial ways, such as to stabilize native forms through hydrogen bonding which serves to help resist denaturation of the protein.
Polyethyleneglycols can be prepared as linear chains, or, by incorporation of multifunctional initiators such as pentaerythritol, can be prepared in non-linear configurations. Linear polyethyleneglycols and other polyalkyleneglycols (e.g., polypropyleneglycols) contain two terminal hydroxyl groups per molecular chain, which are available for chemical bonding, for example with carboxylic acids to form esters. One such group of esters that are well known are the polyethyleneglycol diacrylates, which include diesters of polyethyleneglycol (PEG) with unsubstituted acrylic acid (prop-2-enoic acid) and methacrylic acid (2-methyl-prop-2-enoic acid). These PEG diesters, being acrylates, can themselves undergo polymerization via the acrylate groups to provide ladder-type polymers which can be viewed as at least two or, most likely, many polyacrylate chains crosslinked by the polyethyleneglycol chains. Since a number of different polyacrylate chains can all be crosslinked by the polyethyleneglycol chains and thus all covalently connected to each other, it is believed that the polyethyleneglycolyl polyacrylates have highly three-dimensional structures.
Such materials have been used in a variety of applications, for example, as components of contact lenses (U.S. Pat. No. 5,037,435 and U.S. Pub. No. 2006/0264571), adhesives (U.S. Pat. Nos. 4,404,345 and 6,482,871), electrical insulating resins (U.S. Pat. No. 4,564,646), and dental materials (U.S. Pat. No. 6,315,566); for immobilization of cells and enzymes (U.S. Pat. Nos. 4,177,107 and 4,193,845), and for stent coatings (U.S. Pat. Nos. 6,530,950 and 7,115,691). The polyethyleneglycol diacrylates have also been used for formation of hydrogels containing bioactive compounds for the purpose of drug delivery, including small molecule drugs (R A Scott, N A Peppas (1999), Biomaterials, 20, 1371-1380; J A Diramio et al. (2005), “Poly(ethylene glycol) methacrylate/dimethacrylate hydrogels for controlled release of hydrophobic drugs,” Biotech Prog., 21(4), 1281-8). Polymer compositions formed of polyethyleneglycol polyacrylates wherein poly-glycolic acid segments are covalently bonded within the structure have been studied as for controlled release applications (U.S. Pat. No. 6,602,975). Proteins have been covalently cross-linked to hydrogels formed by polymerization of polyethyleneglycol diacrylates and their rates of release studied (M B Mellott, K Searey, M V Pishko (2001), Biomaterials, 22, 929-941). However, without such covalent bonding of the protein to the polyethyleneglycol polyacrylate framework, long-term controlled release is not observed, as the protein can freely diffuse out of the framework, which does not strongly bind the protein through non-covalent interactions (X Zhao, J M Harris, (2000), J. Pharm. Sci., 87(11), 1450-1458).
Various components have been added to stabilize proteins in formulations against aggregation and formation of unnatural conformations. The use of a naturally occurring polysaccharide as a stabilizer for a protein, encapsulated with a biodegradable polymer, is discussed in U.S. Pat. No. 7,060,299. U.S. Pat. No. 6,998,137 discusses biodegradable polymers including proteins precipitated on sparingly soluble particles, wherein the sparingly soluble particle is selected from the group consisting of zinc carbonate, zinc oxide, zinc tartrate, zinc hydroxide, zinc phosphate, zinc citrate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium oxide, calcium phosphate, calcium sulfate, and calcium carbonate.